Stem-like exhausted CD8 T cells in pleural effusions predict improved survival in non-small cell lung cancer (NSCLC) and mesothelioma

Linda Ye; Heeju Ryu; David Granadier; Long T Nguyen; Yannick Simoni; Ian Dick; Tina Firth; Ebony Rouse; Peter Chiang; Y C Gary Lee; Bruce W Robinson; Jenette Creaney; Evan W Newell; Alec J Redwood

doi:10.21037/tlcr-24-284

Stem-like exhausted CD8 T cells in pleural effusions predict improved survival in non-small cell lung cancer (NSCLC) and mesothelioma

Transl Lung Cancer Res. 2024 Sep 30;13(9):2352-2372. doi: 10.21037/tlcr-24-284. Epub 2024 Sep 27.

Authors

Linda Ye^#¹, Heeju Ryu^#^{2

3}, David Granadier^{2

4}, Long T Nguyen², Yannick Simoni², Ian Dick⁵, Tina Firth¹, Ebony Rouse¹, Peter Chiang¹, Y C Gary Lee^{5

6}, Bruce W Robinson^{1

5

7}, Jenette Creaney^{1

6

7}, Evan W Newell^#², Alec J Redwood^#^{1

5

6}

Affiliations

¹ National Centre for Asbestos Related Diseases, Faculty of Health and Medical Science, University of Western Australia, Nedlands, WA, Australia.
² Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Centre, Seattle, WA, USA.
³ School of Medicine, Sungkyunkwan University, Suwon, Republic of Korea.
⁴ School of Medicine, University of Washington, Seattle, WA, USA.
⁵ School of Biomedical Science, University of Western Australia, Nedlands, WA, Australia.
⁶ Institute for Respiratory Health, University of Western Australia, Nedlands, WA, Australia.
⁷ Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.

^# Contributed equally.

Abstract

Background: Anti-tumor CD8 T cells are important for immunity but can become 'exhausted' and hence ineffective. Tumor-infiltrating exhausted CD8⁺ T cells include less differentiated stem-like exhausted T (Tex^stem) cells and terminally exhausted T (Tex^term) cells. Both subsets have been proposed as prognostic biomarkers in cancer patients. In this study, we retrospectively investigated their prognostic significance in patients with metastatic non-small cell lung cancer (NSCLC) and validated our findings in a mesothelioma cohort.

Methods: Pre-treatment malignant pleural effusions (PEs) from 43 NSCLC (41 non-squamous, 2 squamous) patients were analyzed by flow cytometry. The percentages of Tex^stem and Tex^term CD8 T cells were correlated with overall survival (OS) after adjusting for clinicopathological variables. Findings were validated using a mesothelioma cohort (n=49). Mass cytometry was performed on 16 pre-treatment PE samples from 5 mesothelioma and 3 NSCLC patients for T-cell phenotyping. Single-cell multi-omics analysis was performed on 4 pre-treatment PE samples from 2 NSCLC patients and 2 mesothelioma patients for analysis of the transcriptomic profiles, surface markers and T cell receptor (TCR) repertoire.

Results: Higher frequency of Tex^stem was associated with significantly increased OS [median 9.9 vs. 3.4 months, hazard ratio (HR) 0.36, 95% CI: 0.16-0.79, P=0.01]. The frequency of Tex^term was not associated with OS. These findings were validated in the mesothelioma cohort (high vs. low Tex^stem, median OS 32.1 vs. 19.8 months, HR 0.31, 95% CI: 0.10-0.96, P=0.04). Detailed single-cell sequencing and mass cytometry profiling revealed that exhausted T cells from NSCLC expressed greater stem-likeness and less inhibitory markers than those from mesothelioma and that Tex^stem cells also contained 'bystander' virus-specific T cells.

Conclusions: This study demonstrates that PE CD8 Tex^stem cell abundance is associated with better survival outcomes, and thus may be a useful prognostic biomarker.

Keywords: Non-small cell lung cancer (NSCLC); T cell exhaustion; mesothelioma.

Abstract

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